bims-medica 2025-07-13 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–07–13
nineteen papers selected by
Brett Chrest, Wake Forest University

Gut microbiome changes and cancer immunotherapy outcomes associated with dietary interventions: a systematic review of preclinical and clinical evidence.
The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia.
Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance.
Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations.
PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.
Tracking Hyperpolarized [1-13C] Pyruvate and [1-13C] L-Lactate Metabolism in the Healthy and Post-Stroke Mouse Brain.
Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.
Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism.
An unexpected career in cancer metabolism.
Oxidative Phosphorylation in Uncoupled Mitochondria.
The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
Venetoclax plus azacitidine as genetic-driven bridge-to-transplant therapy for IDH2-mutated acute myeloid leukaemia (AML) refractory to intensive chemotherapy: proof-of-concept case reports.
Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism.
Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.
BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.
Ketogenic Diets Are Associated with an Elevated Risk for All Cancers: Insights from a Cross-Sectional Analysis of the NHANES 2001-2018.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
High-performance genetically-encoded green and red fluorescent biosensors for pyruvate.

J Transl Med. 2025 Jul 08. 23(1): 756

Gut microbiome changes and cancer immunotherapy outcomes associated with dietary interventions: a systematic review of preclinical and clinical evidence.

Csenge Somodi, David Dora, Mátyás Horváth, Gabor Szegvari, Zoltan Lohinai.

   INTRODUCTION: Cancer patient's survival has gradually improved due to immune checkpoint inhibitors (ICIs). Several studies showed a possible association between the intestinal microbiome and ICI efficacy. Strategies for modifying the composition of the gut microbiome encompass various dietary interventions, which may have distinct impacts on the outcomes of ICI-treated patients. In our systematic review, we explored how dietary habits correlate with therapeutic responses in cancer patients and cancer mouse models undergoing immunotherapy.
METHODS: A systematic review was conducted using search terms: "cancer", "immunotherapy", "diet", and "microbiome", from Medline, Web of Science, Scopus, and Cochrane Library databases. The outcomes in the clinical studies were overall response rate (ORR), overall survival (OS), or progression-free survival (PFS) in human studies. In mouse studies, change in tumor size was the endpoint. The comparator attributions were questionnaire-based dietary interventions.
RESULTS: Nineteen articles met the inclusion criteria and were included in the review (6 prospective cohort studies, 1 cross-sectional observational study, and 12 mouse studies). A consistent association was observed between high (vs. low) fiber consumption and improved therapeutic response with a pooled odds ratio of 5.79 when including all human prospective cohort studies. In mice, limited availability of methionine, cysteine, and low intake of leucine and glutamine was linked to reduced tumor progression. Combining ICIs with intermittent fasting or a fasting-mimicking diet significantly decreased tumor volume in mouse melanoma models. In humans, a higher relative abundance of short-chain fatty acid (SCFA) and lactic acid-producing bacteria-particularly Faecalibacterium prausnitzii and Akkermansia muciniphila-correlated with objective response rates (ORR). Similar microbiome alterations were observed in mouse models. Increased fiber intake enhanced ICI efficacy in mice by modulating the gut microbiome, primarily via elevated SCFA production-an effect also reflected in human studies.
CONCLUSION: Intermittent fasting, high fiber, and low sugar consumption are significantly associated with better ICI outcomes. The studies revealed alterations in microbiota composition linked to diet, and these findings were confirmed in animal models, regarding the production of SCFAs and lactic acid, as well as an increase in Bacteroidota/Bacillota ratio and microbial diversity.

Keywords:  Cancer; Diet; Fiber intake; Gut microbiome; Immunotherapy; Ketogenic diet

DOI:  https://doi.org/10.1186/s12967-025-06586-0
Haematologica. 2025 Jul 10.

The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia.

Helong Gary Zhao, Nataly Cruz-Rodriguez, Kent C Johnson, Anthony D Pomicter, Briana Bates, Benjamin Bateman, Torsten Haferlach, Tongjun Gu, Jonathan Ahmann, Dongqing Yan, Greg S Lee, Weiquan Zhu, Jenna Bishop, Shannon J Odelberg, Michael W Deininger.

Metabolic dependencies are emerging as promising therapy targets in cancer, including acute myeloid leukemia (AML). Several metabolic vulnerabilities have been identified in AML cells, including a requirement for balanced sphingolipid metabolism to maintain survival and proliferation. Here we describe a novel function of the RAS superfamily small GTPase ARF6 in maintaining sphingolipid homeostasis in AML. Genetic depletion of ARF6 inhibited the proliferation of AML cell lines and reduced colony formation of primary AML CD34+ cells. Mechanistically, ARF6 promotes conversion of ceramide to sphingomyelin by enhancing sphingomyelin synthase (SGMS1/2) expression, thereby preventing accumulation of cytotoxic ceramide levels. Accordingly, higher expression of ARF6 and its effectors SGMS1/2 in AML patient cells correlates with shorter survival in two independent AML cohorts, with ARF6 exhibiting an adverse prognostic effect independent of European Leukemia Net genetic risk. Small molecule inhibitors of ARF6 suppressed colony formation by primary AML CD34+ cells, but not cord blood CD34+ cells and showed activity in xenograft models. The dependency of AML cells on ARF6 to regulate sphingolipid homeostasis may present a therapeutic opportunity.

DOI: https://doi.org/10.3324/haematol.2024.286228
Mol Metab. 2025 Jul 06. pii: S2212-8778(25)00114-0. [Epub ahead of print] 102207

Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance.

Rocío Rojas, Christian Griñán-Ferré, Aida Castellanos, Ernesto Griego, Marc Martínez, Juan de Dios Navarro-López, Lydia Jiménez-Díaz, José Rodríguez-Álvarez, David Soto Del Cerro, Pablo E Castillo, Mercè Pallàs, Núria Casals, Rut Fadó.

  The ketogenic diet -high in fat and low in carbohydrates- and intermittent fasting have gained popularity not only for weight management but also for their potential to delay cognitive decline associated with neurodegenerative diseases and aging. However, adherence to these diets remains low due to their restrictive nature and undesirable side effects. Both dietary approaches stimulate hepatic production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons. Here, we investigated whether BHB supplementation could mitigate AMPA receptor trafficking impairments, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as a saturated fat-rich diet. Our results show that, in cultured primary cortical neurons, exposure to palmitic acid decreases surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids and BHB increase these levels. Furthermore, physiological concentrations of BHB (1-2 mM) countered the adverse effects of palmitic acid on synaptic GluA1 and GluA2 levels in hippocampal neurons, restoring AMPA receptor-mediated synaptic transmission. In hippocampal slices, BHB also reversed palmitate-induced impairments in excitability and synaptic plasticity (long-term potentiation; LTP). Additionally, daily intragastric administration of BHB (100 mg/kg/day for two months) prevented deficits in recognition and spatial memory induced by a saturated fat-rich diet (49% of calories from fat) in mice. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptor abundance, synaptic function, and neuroplasticity, shedding light on the potential use of BHB as a dietary supplement to counteract cognitive impairments linked to metabolic diseases.

Keywords:  AMPA receptor; beta-hydroxybutyrate; memory; palmitic acid; saturated fatty acid-rich diet; synaptic plasticity

DOI:  https://doi.org/10.1016/j.molmet.2025.102207
Transl Oncol. 2025 Jul 08. pii: S1936-5233(25)00198-6. [Epub ahead of print]59 102467

Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations.

Jie Yang, Yvyin Zhang, Qingshan Li, Peihong Wang.

  We have previously identified sitravatinib as a potent inhibitor of FLT3, capable of overcoming resistance to gilteritinib in the treatment of acute myeloid leukemia (AML). The combination of venetoclax and FLT3 inhibitors gilteritinib and quizartinib has shown promising results in reducing leukemia burden and improving survival in pre-clinical studies and clinical trials of AML with FLT3 mutation. In this study, we aimed to investigate the therapeutic effect of treating AML with sitravatinib combined with venetoclax. Our findings indicated that the combination of sitravatinib and venetoclax significantly decreased cell viability and increased cell apoptosis in AML cell lines harboring FLT3 mutation, more so than either treatment alone. These two agents exerted strong synergistic effects in FLT3-ITD AML cell lines and patient bone marrow cells in vitro. The activation of MAPK/ERK signaling are common causes that weaken the efficacy of FLT3 inhibitors, while the upregulation of anti-apoptotic proteins including BCL-xL and MCL-1 leads to venetoclax resistance. Our data demonstrated that sitravatinib plus venetoclax further suppressed the phosphorylation of AKT and ERK as well as downregulated MCL-1 and BCL-xL, which mechanically explain the synergistic effect. Finally, we tested the potential application of sitravatinib plus venetoclax in vivo using patient-derived xenografts, and found that the combined therapy was significantly more effective in inhibiting leukemia cell expansion, reducing infiltration in the spleen, and prolonging survival time compared to a single administration. Our study demonstrates the potential use of sitravatinib plus venetoclax as an alternative therapeutic strategy to treat AML patients with FLT3-ITD mutation.

Keywords:  BCL-2 inhibitor; FLT3-ITD mutation; Sitravatinib; Synergistic effect; Venetoclax

DOI:  https://doi.org/10.1016/j.tranon.2025.102467
J Exp Clin Cancer Res. 2025 Jul 10. 44(1): 198

PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.

Caterina Mancini, Giulia Lori, Gianluca Mattei, Marta Iozzo, Dayana Desideri, Fabio Cianchi, Laura Fortuna, Federico Passagnoli, Daniela Massi, Filippo Ugolini, Luca Messerini, Salvatore Piscuoglio, Antonio Pezone, Francesca Magherini, Alessio Biagioni, Tiziano Lottini, Demetra Zambardino, Giuseppina Ivana Truglio, Elena Petricci, Alberto Magi, Annarosa Arcangeli, Luisa Maresca, Barbara Stecca, Erica Pranzini, Maria Letizia Taddei.

   BACKGROUND: Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different "non-enzymatic roles" for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC.
METHODS: Overexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model.
RESULTS: PHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models.
CONCLUSIONS: PHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC.

Keywords:  5-Fluorouracil; Chemo-resistance; Colorectal cancer; Hedgehog signaling; Phosphoglycerate dehydrogenase; Serine; Stemness

DOI:  https://doi.org/10.1186/s13046-025-03447-y
NMR Biomed. 2025 Aug;38(8): e70094

Tracking Hyperpolarized [1-13C] Pyruvate and [1-13C] L-Lactate Metabolism in the Healthy and Post-Stroke Mouse Brain.

Thanh Phong Lê, Lara Buscemi, Mario Lepore, Elise Vinckenbosch, Bernard Lanz, Rolf Gruetter, Lorenz Hirt, Jean-Noël Hyacinthe, Mor Mishkovsky.

Tracking hyperpolarized (HP) 13C labeling from either [1-13C] pyruvate or [1-13C] lactate is a useful tool to assess intermediary metabolism in vivo, which has already been translated from preclinical to clinical research. HP [1-13C] pyruvate and [1-13C] lactate provide complementary views on the same metabolic pathway, and both have been tested as potential neuroprotective agents in the context of acute brain injuries, with more convincing evidence for a beneficial effect of lactate. Our aim here was to investigate and compare HP [1-13C] pyruvate and [1-13C] lactate performance as metabolic contrast agents in the brains of healthy mice and mice subjected to middle cerebral artery occlusion, a model of ischemic stroke. We analyzed the metabolite ratios and quantified the real-time apparent kinetic rates of their cerebral metabolism. We found that the cerebral metabolism of both HP [1-13C] pyruvate and HP [1-13C] lactate showed significant alterations after transient cerebral ischemia in mice, reflecting the damage as well as the metabolic reprogramming set in motion to meet the energetic demands in the acute phase of stroke. There was a significant decrease in metabolite ratios (cLPR, cAPR for pyruvate bolus and cPLR, cALR for lactate bolus) and kinetic rates (ckPL for pyruvate bolus and ckLP for lactate bolus). These values progressively decreased from sham to 1 h and 2 h after reperfusion measurements. Overall, while pyruvate is better established as an imaging probe, and lactate appears advantageous on the therapeutic side, both bring information to interrogate brain metabolism in physiological and pathophysiological conditions in real time. This study prepares the ground for further investigation to fully exploit the potential of HP metabolic contrasts for stroke theranostics.

DOI: https://doi.org/10.1002/nbm.70094
Leukemia. 2025 Jul 09.

Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.

Sarah J Skuli, A'ishah Bakayoko, Marisa Kruidenier, Bryan Manning, Paige Pammer, Akmal Salimov, Owen Riley, Gisela Brake-Sillá, Derrick Dopkin, Michael Bowman, Leslie N Martinez-Gutierrez, Colin C Anderson, Julie A Reisz, Roberta Buono, Madhuri Paul, Estelle Saland, Francesca Liccardo, Ann DeVine, Sarah Wong, Jimmy P Xu, Eva Nee, Ryan Hausler, Steffen Boettcher, Said M Sebti, Catherine Lai, Kara N Maxwell, Jean-Emmanuel Sarry, David A Fruman, Angelo D'Alessandro, Clementina Mesaros, Brian Keith, M Celeste Simon, Pamela J Sung, Gerald Wertheim, Nicolas Skuli, Robert L Bowman, Andrew Matthews, Martin Carroll.

Acute myeloid leukemia with mutations in TP53 (TP53mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53mut AML cell lines and primary samples, we determined that TP53mut AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized TP53mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53mut AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.

DOI: https://doi.org/10.1038/s41375-025-02668-6
bioRxiv. 2025 Jul 04. pii: 2025.06.30.662412. [Epub ahead of print]

Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism.

Orion S Willoughby, Anna S Nichenko, Matthew H Brisendine, Niloufar Amiri, Shelby N Henry, Daniel S Braxton, John R Brown, Kalyn S Specht, Adele K Addington, Alexey V Zaitsev, Steven T Burrows, Ryan P McMillan, Haiyan Zhang, Spencer A Tye, Charles P Najt, Siobhan M Craige, Timothy W Rhoads, Junco S Warren, Joshua C Drake.

Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses reveal a compensatory reliance on glucogenic amino acids, particularly alanine and serine, in Ulk1(S555A) mice, with sustained amino acid oxidation during fasting and blunted mitochondrial response to energetic stress. These findings establish Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching and highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility.

DOI: https://doi.org/10.1101/2025.06.30.662412
Nat Cancer. 2025 Jul 08.

An unexpected career in cancer metabolism.

Ralph J DeBerardinis.

DOI: https://doi.org/10.1038/s43018-025-01017-x
Bioessays. 2025 Jul 06. e70038

Oxidative Phosphorylation in Uncoupled Mitochondria.

Henver S Brunetta, Marcelo A Mori, Alexander Bartelt.

  Mitochondrial membrane potential is highly dependent on coupled as well as uncoupled respiration. While brown adipose tissue (BAT) mediates non-shivering thermogenesis (NST), a highly adaptive bioenergetic process critical for energy metabolism, the relationship of coupled and uncoupled respiration in thermogenic adipocytes remains complicated. Uncoupling protein 1 (UCP1)-mediated proton leak is the primary driver of NST, but recent studies have shown that oxidative phosphorylation may be an underappreciated contributor to UCP1-dependent NST. Here, we highlight the role of ATP synthase for BAT thermogenesis and discuss the implications of fine-tuning adrenergic signaling in brown adipocytes by the protein inhibitory factor 1 (IF1). We conclude by hypothesizing future directions for mitochondrial research, such as investigating the potential role of IF1 for mitochondrial substrate preference, structural dynamics, as well as its role in cell fate decision and differentiation.

Keywords:  UCP1; adipocytes; bioenergetics; metabolism; mitochondria; obesity; thermogenesis

DOI:  https://doi.org/10.1002/bies.70038
bioRxiv. 2025 Apr 11. pii: 2025.04.09.647991. [Epub ahead of print]

The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.

Byung Soo Kong, Sehi L'Yi, Erika Gabriela Ramirez-Hernandez, Serin Hong, Rosa Weidenspointner, Suyeon Song, Chase Caserta, Young Min Cho, Nora Kory.

Nicotinamide adenine dinucleotide (NAD + ) is an essential redox cofactor and signaling molecule linked to age-dependent metabolic decline, with its compartmentalization regulated by the mitochondrial carrier SLC25A51. The mechanisms contributing to declining NAD + levels during aging and the consequences of altered NAD + homeostasis across tissues are poorly understood. Here, we show that SLC25A51 is upregulated in aging and aging-associated conditions, particularly in senescent cells. In a mouse model of beta-cell senescence, upregulated SLC25A51 was associated with beta-cell identity loss, senescence progression, and a reduced NAD + /NADH ratio. SLC25A51 was elevated following p16 INK4a -, replicative-, irradiation-, and H 2 O 2 -induced senescence, with NRF2 implicated as a potential transcriptional regulator. Overexpression of SLC25A51, but not a transport-dead mutant, induced senescence factors, while its deletion prevented this effect. Beta-cell-specific deletion of SLC25A51 lowered p16 INK4a levels in pancreatic islets, circulating insulin, and glucose levels, improving insulin sensitivity and indicating its role in cellular senescence and the metabolic control of beta-cell function.

DOI: https://doi.org/10.1101/2025.04.09.647991
Cell Immunol. 2025 Jun 28. pii: S0008-8749(25)00086-3. [Epub ahead of print]414 105000

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.

Annefien Tiggeler, Paul J Coffer.

  Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

Keywords:  Acetyl-CoA; Epigenetic remodelling; Metabolic reprogramming; Nuclear metabolism; T cells

DOI:  https://doi.org/10.1016/j.cellimm.2025.105000
Ann Hematol. 2025 Jul 08.

Venetoclax plus azacitidine as genetic-driven bridge-to-transplant therapy for IDH2-mutated acute myeloid leukaemia (AML) refractory to intensive chemotherapy: proof-of-concept case reports.

Gaetano Cimino, Matteo Caridi, Valeria Cardinali, Sofia Sciabolacci, Sara De Santis, Camilla Rellini, Caterina Matteucci, Cristina Mecucci, Paolo Sportoletti, Francesco Zorutti, Alessandra Carotti, Roberta La Starza, Antonio Pierini, Maria Paola Martelli.

  Despite the greater biological understanding and the new drugs available, acute myeloid leukaemia (AML) patients who are refractory to intensive induction chemotherapy represents an unmet clinical need, especially in young/fit adults who are eligible for bone marrow transplantation. Since venetoclax/azacitidine (ven/aza) was introduced in AML management in 2020, survival of elderly/unfit patients has dramatically improved, especially in those carrying NPM1 or IDH2 mutations. However, the use of ven/aza in young and fit adults remains limited, raising ongoing debate about its potential role beyond patients ineligible to intensive chemotherapy. Here, we discuss three under 60 years chemorefractory AML patients, who, given the concomitant IDH2 mutations, were started to ven/aza as bridge-to-transplant and successfully treated. These cases confirm the extraordinary sensitivity of IDH2-mutated AML to aza/ven even in the refractoriness setting and show that such less-intensive regimen can be driven by genetics offering a promising alternative to intensive salvage chemotherapy, while preserving patient fitness for allo-transplant.

Keywords:  AML; Allo-HSC; Azacitidine/venetoclax; IDH2; Relapse/refractoriness; Salvage treatment

DOI:  https://doi.org/10.1007/s00277-025-06500-0
Am J Physiol Cell Physiol. 2025 Jul 11.

Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism.

Osvaldo Rodrigues Pereira, Julian D C Serna, Camille C Caldeira da Silva, Henrique Camara, Sean D Kodani, William T Festuccia, Yu-Hua Tseng, Alicia J Kowaltowski.

  Brown adipose tissue (BAT) plays a central role in mammalian non-shivering thermogenesis, dissipating mitochondrial membrane potentials through the activity of uncoupling protein UCP1 to release heat. Inner membranes of mitochondria are known to be permeable to potassium ions (K+), which enter the matrix either through ATP-sensitive channels (MitoKATP) or leakage across the bilayer driven by inner membrane potentials. Mitochondrial K+ influx is associated with increased osmotic pressure, promoting water influx and increasing matrix volume. Since BAT mitochondria have lower inner membrane potentials due to uncoupling protein 1 (UCP1) activity, we hypothesized this could involve compensatory changes in MitoKATP activity, and thus tested MitoKATP involvement in brown adipocyte activities under basal and stimulated conditions. We find that cold exposure and adrenergic stimulation in mice modulate BAT MitoK levels, the channel portion of MitoKATP. Genetic ablation of the gene that codes for the pore-forming subunit of MitoKATP in human pre-adipocytes decreased cellular respiration and proliferation, compromising differentiation into mature adipocytes. In mouse cell lines, the absence of the protein limited cellular oxygen consumption in the precursor stage, but not in mature adipocytes. Interestingly, inhibition of MitoKATP in mature adipocytes increased adrenergic-stimulated oxygen consumption, indicating that shutdown of this pathway is important for full BAT thermogenesis. Similarly, MitoKATP inhibition increased oxygen consumption in BAT mitochondria isolated from mice treated with beta 3 adrenergic receptor agonist CL316,243. Overall, our results suggest that the activity of MitoKATP regulates differentiation and metabolism of brown adipocytes, impacting on thermogenesis.

Keywords:  K+ transport; brown adipose tissue; mitochondria; thermogenesis; uncoupling

DOI:  https://doi.org/10.1152/ajpcell.00070.2025
Adv Sci (Weinh). 2025 Jul 11. e02402

Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.

Chuman Lin, Zhiyang Li, Xiaotong Zhu, Wanbing Zhou, Xiansheng Lu, Jiali Zheng, Jie Lin.

  The abnormal arginine metabolism is characteristic of tumor cell metabolism in colorectal cancer (CRC). However, the mechanisms underlying arginine metabolic reprogramming and how altered metabolism in turn enhances CRC tumorigenicity are poorly understood. Protein post-translational modifications (PTMs) are crucial for regulating protein function, activity, and interactions. Here, the study reports that arginine levels are elevated in CRC, accompanied by the high expression of arginase-1 (ARG1) but low levels of ARG1 β-hydroxybutyrylation (Kbhb) and its oncogenic role in CRC in a catalytic-activity-independent manner. Mechanistically, low-level ARG1-Kbhb-induced arginine metabolic reprogramming by decreasing the interaction of ARG1 with SLC3A2 in CRC cells inhibits the efflux of arginine, thereby increasing intracellular arginine levels to promote tumorigenicity. P300 is identified as the "writer" of Kbhb. Inducing ARG1-Kbhb at the Lys313 residue by β-hydroxybutyrate (BHB) promotes the interaction of ARG1 with SLC3A2, resulting in the efflux of arginine in CRC cells. Together, these findings reveal valuable insights into arginine metabolism reprogramming involving the ARG1-Kbhb/P300/SLC3A2 signaling axis, thereby bridging the connection between metabolic reprogramming and PTMs, which may shed light on the therapeutic potential of combining BHB with ARG1 inhibitor through the conventional enzymatic role and nonenzymatic metabolic function of ARG1 for CRC.

Keywords:  ARG1; arginine metabolism reprogramming; colorectal cancer; β‐hydroxybutyrylation

DOI:  https://doi.org/10.1002/advs.202502402
Mol Cancer Ther. 2025 Jul 10.

BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.

Rebecca A DeStefanis, Alexa E Schmitz, Alyssa K Steimle, Susan N Payne, Gioia C Sha, Autumn M Olson, Alec Cornelio, Anna E L Lippert, Sean G Kraus, Katherine A Johnson, Peter F Favreau, Amani Gillette, Christopher Babiarz, Devon Miller, Carley M Sprackling, Cheri A Pasch, Stephanie Pritzl, Dana R Van De Hey, Demetra P Korkos, Tyler M Foley, Alexander E Yueh, Aurora L J X Greane, Linda Clipson, Melissa C Skala, Dustin A Deming.

Targeting PIK3CA mutant colorectal cancers (CRCs) with precision medicine strategies is of great clinical interest. However, resistance to single agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of MTORC1/2 is necessary to induce a response in PIK3CA mutant CRCs. The PI3K/MTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA mutant solid tumors as part of the NCI MATCH trial. Here we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA mutant CRCs. Using a novel high-throughput drug screen method in Apc and Pik3ca mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-1096
Nutr Cancer. 2025 Jul 10. 1-11

Ketogenic Diets Are Associated with an Elevated Risk for All Cancers: Insights from a Cross-Sectional Analysis of the NHANES 2001-2018.

Yuping Liu, Xiaolong Qu, Dingsheng Liu, Dongming Yang.

Ketogenic diet (KD) has increasingly been applied in anti-cancer therapy in recent years; however, its effect on cancer development risk remains controversial. We examined the association between dietary ketogenic ratio (DKR) and cancer incidence using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2001 and 2018. Dietary intake information was collected via a detailed 24-h dietary recall survey, and DKR values were calculated using a specialized formula. Multivariate logistic regression analysis was performed to evaluate the correlation between DKR and tumor occurrence, with restricted cubic splines (RCS) utilized to assess potential nonlinear relationships. Furthermore, a two-stage linear regression analysis was carried out to determine the inflection point. Furthermore, subgroup analyses were conducted stratified by demographic variables, including age, gender, race, body mass index (BMI), smoking status, and diabetes mellitus. A significant association was observed between DKR and cancer risk in multivariate logistic regression models fully adjusted for all potential confounding factors (OR, 1.58; 95%CI: 1.08, 1.54; p = 0.049). Moreover, individuals in the highest quartile of DKR exhibited a significantly increased risk for all cancers compared to those in the lowest quartile (Q4: OR, 1.29; 95%CI: 1.08, 1.34; p = 0.005). The RCS analysis revealed a non-linear relationship between DKR and cancer risk (p < 0.001, P for nonlinear trend = 0.003), with a turning point identified at 0.44 units on the scale used in this study. Piecewise regression analysis based on this threshold indicated that DKR values below 0.44 (DKR < 0.44) were significantly associated with an increased risk for all cancers within the context of this investigation (OR, 1.08; 95%CI: 1.04, 1.12; p < 0.001), while no significant correlation was observed for DKR values above this threshold (DKR ≥ 0.44) (OR, 1.01; 95%CI: 0.95, 1.07; p = 0.77). Furthermore, the findings from the subgroup analyses were consistent with the overall results. Therefore, we conclude that a KD might elevate the risk for all cancers, and further studies are warranted to validate this hypothesis.

DOI: https://doi.org/10.1080/01635581.2025.2497095
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
bioRxiv. 2025 Jul 05. pii: 2025.04.17.649293. [Epub ahead of print]

High-performance genetically-encoded green and red fluorescent biosensors for pyruvate.

Shosei Imai, Saaya Hario, Carl Suerte, Issei Yamaguchi, Kenryo Sakoi, Adam Thuen, Brekken Meznarich, Mikhail Drobizhev, Takuya Terai, Kei Takahashi-Yamashiro, Robert E Campbell.

Pyruvate is the end-product of glycolysis and a central metabolite involved in many biochemical pathways. However, a lack of high-performance (i.e., Δ F / F 0 > 10) single fluorescent protein (FP)-based biosensors has hindered efforts to investigate the physiological role of pyruvate. Here, we present the GreenPy1 and ApplePy1 series, which are green FP (GFP)-based and red FP (RFP)-based pyruvate biosensors, respectively. Both series exhibit large fluorescence intensity change (Δ F / F 0 ∼ 20 to >40) and a range of affinities (10s of μM to several mM). We demonstrate the utility of these pyruvate biosensors for multicolor imaging of metabolite concentration changes in mammalian cells.

DOI: https://doi.org/10.1101/2025.04.17.649293